Process for the manufacture of vortioxetine HBr alpha-form

a technology of vortioxetine and alpha-form, which is applied in the field of process for the manufacture of vortioxetine hbr alpha-form, can solve the problems of limiting the industrial applicability of vortioxetine, acid hydrolysis of the solvent, and time and energy-consuming process

Active Publication Date: 2021-09-21
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These processes are characterised by a number of features which may limit their industrial applicability.
The use of the solvent ethyl acetate in a strongly acidic environment (after addition of aqueous HBr) may result in acid hydrolysis of the solvent.
Such process is time and energy demanding.
Still other processes apply several solvents sequentially and long process time which together add to the overall process complexity.

Method used

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  • Process for the manufacture of vortioxetine HBr alpha-form
  • Process for the manufacture of vortioxetine HBr alpha-form
  • Process for the manufacture of vortioxetine HBr alpha-form

Examples

Experimental program
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example 1 (

Reference)

[0064]To a 2 L three necked flask equipped with mechanical stirring, a thermometer and a reflux condenser was added toluene (600 mL) and vortioxetine (100 g, 0.335 mol). The mixture was heated with a heating mantle to 65° C. and water (27 mL, 1.5 mol) was added to obtain a clear solution. The heating mantle was removed and aqueous HBr (48%, 39.8 mL (59.3 g), 0.352 mol) was added. The flask was cooled immediately on ice / water. After few minutes at a temperature of 50-55° C. precipitation started. Stirring was continued and the mixture was allowed to cool to 5° C. over the next 20 min. Stirring was continued for further 20 min. The precipitated product was isolated by filtration, washed on the filter with toluene (3×40 mL) and dried in vacuo at 40° C. over-night. Yield 126.0 g. NMR showed presence of very little toluene. XRPD showed that the isolated product was a mixture of vortioxetine HBr α-form and β-form. The XRPD obtained is shown in FIG. 1.

example 2 (

Reference)

[0065]Vortioxetine HBr (1.0 gram, 2.64 mmol) was attempted dissolved in toluene (6.0 mL) and water (0.27 mL) by heating the mixture to reflux for 5 minutes; however a clear solution was not obtained. More toluene (12 mL) and water was added (0.54 mL). The clear mixture was crash-cooled on an ice / NaCl mixture and stirred for 30 min. The precipitate was isolated by filtration and washed with toluene (3×1 mL) on the filter and dried in vacuo at room temperature overnight. Yield: 1.1 gram. XRPD showed that pure vortioxetine HBr 3-form was obtained. The XRPD obtained is shown in FIG. 2.

example 3 (

Reference)

[0066]Vortioxetine (1.0 gram, 3.35 mmol) was dissolved in toluene (6.0 mL) and water (0.27 mL) by heating the mixture to 65° C. Aqueous HBr (48%, 0.4 mL (0.59 g), 3.52 mmol) was added and the mixture was crash-cooled on an ice / NaCl mixture (to −15° C.) over 10 minutes and stirred for an additional 30 min. The precipitate was isolated by filtration and washed with toluene (3×2 mL) on the filter and dried in vacuo at room temperature overnight. Yield: 1.16 gram. XRPD showed that the product obtained was a mixture of vortioxetine HBr α-form, vortioxetine HBr hydrate and an unidentified component. Moreover, XRPD indicated a low degree of crystallinity. The XRPD obtained is shown in FIG. 3.

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Abstract

A process for the manufacture of vortioxetine HBr α-form is provided.

Description

CROSS REFERENCE TO PRIOR APPLICATIONS[0001]This is a U.S. National Phase application under U.S.C. § 371 of International Patent Application No. PCT / EP2018 / 060192, filed Apr. 20, 2018, which claims the benefit of DK Application No. PA201700264, filed Apr. 25, 2017. The International Application was published on Nov. 1, 2018 as International Publication No. WO 2018 / 197360 under PCT Article 21(3). The contents of the above applications are incorporated herein in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to a manufacturing process for a specific polymorphic form of the vortioxetine HBr salt.BACKGROUND OF THE INVENTION[0003]International patent applications including WO 03 / 029232 and WO 2007 / 144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof. WHO has since published that vortioxetine is the recommended International Non-proprietary Name (INN) for 1-[2-(2,4-dimethyl-phenylsulfanyl)...

Claims

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Application Information

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Patent Type & AuthorityPatents(United States)
IPC IPC(8): C07D295/096C07D295/08
CPCC07D295/096C07D295/08C07B2200/13C07D295/06
InventorPETERSEN, HANS
OwnerH LUNDBECK AS